Number of centromeric signals in micronuclei and mechanisms of aneuploidy

Abstract

Genome instability or changes in chromosome structure and number are important facets of oncogenesis. Aneuploidy is a major cause of human reproductive failure and plays a large role in cancer. It is therefore important that any increase in its frequency due to occupational exposure to mutagens and carcinogens should be recognized and controlled. In recent years, the cytokinesis-block micronucleus assay has emerged as a biomarker of chromosome/genome damage relevant to cancer. Fluorescent in situ hybridisation using human pancentromeric DNA probes discriminates between the presence of acentric chromosomal fragments and whole chromosomes in binucleated micronucleated lymphocytes. The separated analysis of centromeric micronuclei may improve the sensitivity of the micronucleus assay in detecting genotoxic effects and chromosome instability. Our previous findings suggest that aneugenic events leading to micronuclei (MN) containing a single centromere (C1+MN) and two or more centromeres (Cx+MN) may arise through different pathways. Chromosome migration impairment would lead to increased C1+MN frequency whereas centrosome amplification would induce Cx+MN with three or more centromeric signals. Additional studies that target cellular defects on the centrosome (microtubule nucleation, organization of the spindle poles, cell cycle progression) are required to better understand aneuploid cell production.